JP2001106664A - Production of optically active imino alcohol compounds and amino alcohol compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a practical method for producing an optically active β-amino alcohol having an anti-configuration from an easily available α-iminocarbonyl compound as a starting raw material. SOLUTION: This method for producing an optically active β-amino alcohol of the formula: Ra-C*H(OH)-C*H(NH2)-Rc has a process for making hydrogen to act on a compound of the formula: Ra-Co-C(=NORb)-Rc in the presence of an optically active transition metal compound and a base to obtain the optically active β-iminoalcohol of the formula: Ra-C*H(OH)-C(=NORb)-Rc and a process for reducing the obtained β-iminoalcohol (in these formulas, Ra, Rb and Rc are each an alkyl, an alkenyl, a cycloalkyl, an aralkyl or an aryl which may have one or more substituents, respectively, or the like; C* is asymmetric carbon atom).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active β-amino alcohol, particularly an optically active β-amino alcohol having an anti-configuration, which is useful as an intermediate for the synthesis of pharmaceuticals, agricultural chemicals, catalysts, etc. from α-aminocarbonyl compounds. The present invention relates to a method for producing an alcohol with high yield and high enantio- and diastereoselectivity, and a method for producing an optically active β-imino alcohol which is an intermediate for the production.

[0002]

2. Description of the Related Art Conventionally, an optically active β-amino alcohol,
In particular, as a method for producing an optically active β-amino alcohol having an anti-stereo configuration, (1) a method using an optically active α-amino acid as a raw material, and (2) a method using an olefin as a raw material are relatively general. (See, for example, Chemical Rev., 96 , 8).
35 (1996)).

Of the above methods, (1) the optical activity α
In the method using amino acids as a raw material, α-amino acids as raw materials can be obtained by industrial catalytic chemical synthesis, biological synthesis or resolution, but optically active α can be obtained at low cost.
-Limited amino acids.

As a method for deriving an optically active β-amino alcohol from an α-amino acid, the amino group of the α-amino acid is protected, and then a carboxylic acid is reduced to cause a nucleophilic reaction with a ketone. Anti-configuration optically active β-
A method for producing amino alcohols is known (for example, Tetrahedon Lett., 31 , 498).
5 (1990). ). However, this method has a problem that an equivalent amount of a metal reagent is used in both the reduction reaction and the nucleophilic reaction, and the yield and selectivity are insufficient. As described above, the method of synthesizing from an α-amino acid has disadvantages in both raw materials and production methods.

As the method (2) using an olefin as a raw material, there has been known a method of asymmetric aminohydroxylation of an olefin having a cis configuration to synthesize an optically active β-amino alcohol having an anti configuration (for example, see, for example). , Ang
ew. Chem. Int. Ed. Engl. , 35 , 4
51 (1996) and the like. ). However, this method is not always preferable because it is difficult to obtain a cis olefin as a raw material and only a product having a protecting group that is difficult to be eliminated is obtained.

[0006] As (3), a method using α-imino ketone as a raw material is disclosed in J. Am. Org. Chem. , 54 , 2
021 (1989) and the like, but it is an effective method only for a limited number of substrates, and has poor generality.

[0007] In addition, an asymmetric reduction of α-imino ketone using an oxazaborolidine derived from a certain optically active amino alcohol and boron as an auxiliary group to give an optically active β-amino alcohol having an anti-configuration. Are also known (eg, Tetrahedro)
n Lett. , 39 , 5195 (1998). ). However, this method has difficulty in separating the amino alcohol used for the auxiliary group and the product,
There is a problem as an industrial manufacturing method.

[0008] As described above, the optically active β
-High generality of producing amino alcohols, high yield, and highly selective production method has not yet been established,
In particular, development of a method for producing optically active β-amino alcohols having the anti-stereo configuration has been desired.

[0009]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above circumstances, and uses an easily available α-iminocarbonyl compound as a starting material, and provides an optically active β-amino alcohol having an anti-configuration. It is intended to provide a practical production method for

[0010]

According to the present invention, there is firstly provided a compound represented by the following general formula (1):

[0011]

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(Wherein Ra, Rb and Rc each independently represent an alkyl group which may have a substituent, an alkenyl group which may have a substituent, A cycloalkyl group, an aralkyl group which may have a substituent or an aryl group which may have a substituent, wherein Ra and Rc or Rb and Rc are bonded to form a 5- to 8-membered group; May form a ring.), In the presence of an optically active transition metal compound and a base, with hydrogen.
General formula (2)

[0013]

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(Wherein Ra, Rb and Rc have the same meaning as described above, and C * represents an asymmetric carbon atom.) The present invention provides a method for producing an optically active β-imino alcohol represented by the formula:

Further, the present invention provides, secondly, general formula (1)

[0016]

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(Wherein Ra, Rb and Rc each independently represent an alkyl group which may have a substituent, an alkenyl group which may have a substituent, A cycloalkyl group, an aralkyl group which may have a substituent or an aryl group which may have a substituent, wherein Ra and Rc or Rb and Rc are bonded to form a 5- to 8-membered group; May form a ring), and reacting the α-iminocarbonyl compound represented by the general formula (2) with hydrogen in the presence of an optically active transition metal compound and a base.

[0018]

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Wherein Ra, Rb and Rc have the same meaning as described above, and C * represents an asymmetric carbon atom.
-Obtaining an imino alcohol, and reducing the obtained β-imino alcohol.
General formula (3)

[0020]

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(Wherein Ra, Rc and C * have the same meanings as described above). The present invention provides a method for producing an optically active β-amino alcohol having an anti-configuration.

In the first and second inventions, the optically active transition metal compound is preferably a homogeneous optically active hydrogenation catalyst,

The above-mentioned optically active homogeneous hydrogenation catalyst is more preferably

[0024]

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Wherein Ma represents a Group VIII metal;
Y each independently represents a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group or an alkoxy group;
Represents each independently 0 or an integer of 1 to 4;
x represents a phosphine ligand, and Nx represents an amine ligand. ).

In the compound represented by the general formula (4), Px is preferably an optically active phosphine ligand, and Nx is preferably an optically active amine ligand. Is more preferably an optically active ligand.

In the first and second inventions, the base is represented by the general formula (5)

[0028]

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(Wherein, Mb represents an alkali metal or an alkaline earth metal, and Z represents a hydroxyl group, an alkoxy group or a mercapto group).

In the second aspect, the step of reducing the β-imino alcohol preferably includes a step of causing hydrogen to act on the β-imino alcohol represented by the general formula (2). Preferably, the method includes a step of allowing hydrogen to act on the β-imino alcohol represented by the general formula (2) in the presence of a metal-based reagent, wherein the metal-based reagent includes a heterogeneous metal catalyst or a metal. More preferably, a hydride is used.

The step of reducing the β-imino alcohol preferably comprises the step of reducing the β-imino alcohol represented by the general formula (2).
The method includes a step of causing a boron compound to act on imino alcohol, and it is more preferable to use borane as the boron compound.

[0032]

Embodiments of the present invention will be described below in detail. In the raw material compound represented by the general formula (1) of the present invention,

Ra, Rb and Rc are each independently an alkyl group which may have a substituent, an alkenyl group which may have a substituent, and a cycloalkyl which may have a substituent. Represents an aralkyl group which may have a group, a substituent or an aryl group which may have a substituent.

Examples of the alkyl group of the linear or branched alkyl group which may have a substituent include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl,
Octyl, nonyl, decyl, dodecyl group, etc.
20 alkyl groups can be exemplified.

The alkenyl group of the linear or branched alkenyl group which may have a substituent includes vinyl, 1-propenyl, 2-propenyl, 1-butenyl,
1-isopropenyl, 2-butenyl, 3-butenyl,
Examples thereof include alkenyl groups having 2 to 20 carbon atoms, such as 1,3-butadienyl, 1-pentenyl, 2-pentenyl, and 3-pentenyl.

Examples of the cycloalkyl group of the optionally substituted cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. .

The aralkyl group of the aralkyl group which may have a substituent includes, for example, a aralkyl group having 7 to 20 carbon atoms such as benzyl, α-methylbenzyl, α, α-dimethylbenzyl and α-ethylbenzyl. An aralkyl group can be mentioned.

The aryl group of the aryl group which may have a substituent includes phenyl, 1-naphthyl, 2
-Aromatic hydrocarbon groups such as naphthyl group, furanyl, pyranyl, oxygen-containing heterocyclic group such as dioxolanyl, sulfur-containing heterocyclic group such as thienyl,

Includes saturated or unsaturated such as pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, pyridyl, pyradadyl, pyrazinyl, benzimidazolyl, benzpyrazolyl, benzozoazolyl, quinolyl, anthranyl, indolyl, phenanthrinylyl and the like. A nitrogen heterocyclic group can be exemplified.

The above-mentioned linear or branched alkyl group which may have a substituent, the linear or branched alkenyl group which may have a substituent, and the cycloalkyl group which may have a substituent As the substituent of the aralkyl group which may have a substituent or the aryl group which may have a substituent, as long as the substituent does not inhibit the reaction, the substitution position and the substituent Is not particularly limited.

Examples of such a substituent include a hydroxy group, a carboxyl group, an amino group, a nitro group, methyl,
Ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, hexyl and other alkyl groups, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and other alkoxy groups, methoxycarbonyl, ethoxycarbonyl , Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, alkoxycarbonyl groups such as t-butoxycarbonyl group,

A phenyl group which may have a substituent at any position of the benzene ring, a naphthyl such as a 1-naphthyl or 2-naphthyl group which may have a substituent at any position of the naphthalene ring. Groups, furan, pyran, dioxolan, dioxane, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, triazole, thiazole, isothiazole, pyridine, pyridazine, pyrazine, heterocycle such as benzimidazole, benzopyrazole, benzothiazole, quinoline Groups (these groups may have a substituent at any position),
And halogen atoms such as fluorine, chlorine, and bromine.

Further, Ra and Rc or Rb and Rc may combine to form a 5- to 8-membered ring. In such a case, examples of the compound represented by the general formula (1) include:
The following compounds (a) to (d) can be exemplified. In the formula, Ra and Rb represent the same meaning as described above.

[0044]

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The transition metal compound used in the present invention is preferably a homogeneous hydrogenation catalyst. As such a homogeneous hydrogenation catalyst, for example, complexes of transition metals of Group VIII elements of the periodic table such as Ru, Rh, Ir, and Pt are preferable. These transition metal compounds are described, for example, in Angew. Che
m. Int. Ed. , 37 , 1703 (1998) and the like.

The transition metal compound is represented by the following general formula (4)
More preferably, it is a transition metal complex represented by

[0047]

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In the formula (4), Ma represents Ru, Rh, Ir,
Represents a Group VIII metal such as Pt. Among these, Ru (II) or Ru (II) from the viewpoint of stability of the complex and availability.
The complexes of I) are particularly preferred.

X and Y are the same or different and each represents a hydrogen atom, a halogen atom such as fluorine, chlorine, bromine, a carboxyl group, a hydroxyl group, methoxy, ethoxy, propoxy,
Represents an anion such as an alkoxy group such as an isopropoxy group or a butoxy group.

Px represents a phosphine ligand, for example,
A phosphorus monodentate ligand represented by the general formula: PR ¹ R ² R ³ , a phosphorus bidentate ligand represented by the general formula: R ⁴ R ⁵ P-W-PR ⁶ R ⁷ and the like are exemplified. be able to.

The above general formula: R ⁴ R ⁵ P-W-PR ⁶ R ⁷
In the above, R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each represents an alkyl group, a phenyl group or a cycloalkyl group which may have a substituent, and R ⁴ and R ⁵ or R ⁶ and R ⁷ may be combined with P to form a P-containing cyclic group which may have a substituent.

W is an alkylene group having 1 to 5 carbon atoms such as methylene, ethylene, propylene and butylene; an alkylidene group having 1 to 5 carbon atoms such as ethylidene and propylidene; and a carbon atom such as cyclopentylene and cyclohexylene. 3
A cycloalkylene group of -8, a cycloalkylidene group having 3 to 8 carbon atoms, an aryl group such as o-phenylene, m-phenylene, p-phenylene, or an unsaturated hydrocarbon group.

When PR ¹ R ² R ³ is optically active, at least one of R ¹ , R ² , R ³ is an optically active group (ie, at least one of R ¹ , R ² , R ³ ) When one group is a substituent having an asymmetric carbon atom), R ¹ , R
² and R ³ all consist of different substituents (ie, P
Is an asymmetric center).

Examples of the monodentate phosphine ligand represented by the above general formula: PR ¹ R ² R ³ include, for example, trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, tricyclohexylphosphine, tri (p- Tolyl) phosphine, diphenylmethylphosphine, dimethylphenylphosphine, isopropylmethylphosphine, cyclohexyl (O-anisyl) -methylphosphine, 1- [2- (diphenylphosphino) ferrocenyl] ethyl methyl ether,
(Diphenylphosphino) -2′-methoxy-1,1 ′
-Tertiary phosphines such as binaphthyl are preferred.

Examples of the racemic or optically active bidentate phosphine ligand represented by the above general formula: R ⁴ R ⁵ P—W—PR ⁶ R ⁷ include bisdiphenylphosphinomethane and bisdiphenylphosphinoethane. And bidentate tertiary phosphine compounds such as bisdiphenylphosphinopropane, bisdiphenylphosphinobutane, bisdimethylphosphinoethane, and bisdimethylphosphinopropane.

As available bidentate phosphine ligands:
For example, BINAP: 2,2'-bis- (diphenylphosphino) -1,1'-binaphthyl, BINA having an alkyl or aryl group substituent on the naphthyl ring of BINAP
P derivatives, for example, BINAP derivatives having 1 to 5 substituents such as an alkyl group on a benzene ring bonded to a phosphorus atom such as H8BINAP, BINAP, for example, TolBI
NAP: 2,2'-bis (di-3-tolylphosphino)
-1,1′-binaphthyl or 2,2′-bis (di-4
-Tolylphosphino) -1,1′-binaphthyl, Xyl
yl-BINAP: 2,2′-bis- (di-3,5-xylylphosphino) -1,1′-binaphthyl, and further B
ICHEP: 2,2'-bis- (dicyclohexylphosphino) -6,6'-dimethyl-1,1'-biphenyl, BPPFA: 1- [1 ', 2-bis- (diphenylphosphino) ferrocenyl] ethyldiamine , CHIR
APHOS: 2,3-bis- (diphenylphosphino)
Butane, CYCPHOS: 1-cyclohexyl-1,2
-Bis- (diphenylphosphino) ethane, DEGPH
OS: 1-substituted-3,4-bis- (diphenylphosphino) pyrrolidine, DIOP: 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis- (diphenylphosphino) butane, DIPAMP : 1,2-bis [(O-methoxyphenyl) phenylphosphino] ethane, DuPHOS: (substituted-1,2-bis (phosphorano) benzene), NORPHOS: 5,6-bis- (diphenylphosphino) -2 -Norbornene, PNNP:
N, N'-bis- (diphenylphosphino) -N, N '
-Bis [1-phenylethyl] ethylenediamine, PR
OPHOS: 1,2-bis- (diphenylphosphino)
Propane, SKEWPHOS: 2,4-bis- (diphenylphosphino) pentane and the like can be mentioned. Further, a BINAP derivative having a fluorine substituent can be used.

Of course, the phosphine ligand that can be used in the present invention is not limited to these as long as it can form a metal complex stably.

As the amine ligand Nx, a nitrogen monodentate ligand represented by the general formula: NR ⁸ R ⁹ R ¹⁰ or a general formula: R ¹¹ R ¹² NV—NR ¹³ R ¹⁴ And the like diamine ligands and the like.

The above general formula: NR⁸ R⁹ R^TenIn, R
⁸, R⁹, R^TenAre the same or different and are hydrogen, alkyl
Group, aryl group or unsaturated hydrocarbon group,⁸ , R
⁹ , R ^TenAny two of which have a substituent together
May form an alicyclic group which may be substituted. Also, R⁸ ,
R⁹ , R^TenEven if at least one of the is an optically active group
Good. V is a divalent hydrocarbon group having 1 to 5 carbon atoms;
Cyclohydrocarbon group, divalent aryl group or divalent unsaturated
Represents a hydrocarbon group or the like.

The above general formula: R ¹¹ R ¹² NV-NR ¹³ R ¹⁴
In the formula, R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are the same or different and each represent hydrogen, an alkyl group, an aryl group or an unsaturated hydrocarbon group, and R ¹¹ and R ¹² or R ¹³ and R ¹⁴ together To form an alicyclic group which may have a substituent.

The monoamine ligand represented by the above general formula: NR ⁸ R ⁹ R ¹⁰ includes methylamine, ethylamine, propylamine, butylamine, pentylamine,
Hexylamine, cyclopentylamine, cyclohexylamine, benzylamine, dimethylamine, diethylamine, dipropylamine, dihexylamine, dicyclopentylamine, dicyclohexylamine, dibenzylamine, diphenylamine, phenylethylamine,
Monoamine compounds such as proline and piperidine can be exemplified.

Further, examples of the optically active monoamine ligand include optically active monoamine compounds such as optically active phenylethylamine, naphthylethylamine, cyclohexylamine and cycloheptylethylenediamine.

V is methylene, ethylene, propylene,
An alkylene group having 1 to 5 carbon atoms such as butylene, an alkylidene group having 1 to 5 carbon atoms such as ethylidene and propylidene,
3-8 carbon atoms such as cyclopentylene and cyclohexylene
A cycloalkylene group having 3 to 8 carbon atoms, an aryl group such as o-phenylene, m-phenylene, p-phenylene, or an unsaturated hydrocarbon group.

The above formula: R ¹¹ R ¹² NV—NR ¹³ R ¹⁴
Methylene diamine, ethylene diamine, 1,2-diaminopropane, propylene diamine, 1,3-diaminopropane, 1,4
-Diaminobutane, 2,3-diaminobutane, 1,2-
Cyclopentanediamine, 1,2-cyclohexanediamine, N-methylethylenediamine, N, N′-dimethylethylenediamine, N, N, N′-trimethylethylenediamine, N, N, N ′, N′-tetramethylethylenediamine, o- Examples thereof include phenylenediamine and p-phenylenediamine.

In the present invention, an optically active diamine can also be used. Examples of such optically active diamine diamine include 1,2-diphenylethylenediamine, 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3-dimethylbutanediamine, 1,2-dimesitylethylenediamine, -Methyl-2,2-diphenylethylenediamine, 1-isobutyl-2,2-diphenylethylenediamine, 1-isopropyl-2,2-diphenylethylenediamine, 1-methyl-2,2-di (p-methoxyphenyl) ethylenediamine, -Isobutyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-isopropyl-2,2
-Di (p-methoxyphenyl) ethylenediamine, 1-
Benzyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-methyl-2,2-dinaphthylethylenediamine, 1-isobutyl-2,2-dinaphthylethylenediamine, 1-isopropyl-2,2-dinaphthylethylenediamine And other optically active diamine compounds.

Of course, the optically active diamine compound is not limited to the exemplified optically active diamine derivatives, and furthermore, optically active propanediamine, butanediamine, phenylenediamine, cyclohexanediamine derivatives and the like can be used.

The amine ligand that can be used in the present invention is not limited to these as long as it can form a metal complex stably. Further, at least one of the phosphorus ligand and the amine ligand may be optically active, and these can be used in an appropriate combination.

In the present invention, the amount of the homogeneous hydrogenation catalyst used varies depending on the type of the reaction substrate, the reaction vessel and the economical efficiency, etc., but the molar ratio is 1/100 to carbonyl compound as the reaction substrate. Within the range of 1 / 1,000,000, more preferably 1/200 to 1 / 100,00.
It is in the range of 0.

The base used in the present invention includes:
It is preferable to use a compound represented by the following general formula (5).

[0070]

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In the formula (5), Mb represents an alkali metal or an alkaline earth metal, and Z represents a hydroxyl group, an alkoxy group,
Represents a mercapto group or a naphthyl group.

As such a base, for example, KOH, K
OCH ₃ , KOCH (CH ₃ ) ₃ , KOC (CH ₃ ) ₃ , KC
₁₀ H ₈ , NaOH, NaOCH ₃ , LiOH, LiOC
_{H 3, LiOCH (CH 3)} 2, Mg (OC 2 H 5) 2, Na
SH and the like can be exemplified. In the present invention, a quaternary ammonium salt can also be used as a base.

The amount of the base varies depending on the type of the transition metal complex of Group VIII and the type of the reaction substrate, but is usually about 2 equivalents per 1 equivalent of the catalyst and 0 to 1.1 equivalents per 1 equivalent of the substrate. The degree is preferred.

Formula (1): Ra-C (= O) -C (=
From an α-iminocarbonyl compound represented by NORb) —Rc, a compound represented by the general formula (2): Ra—C * H (OH) —C (=
The reaction for obtaining the β-imino alcohol represented by NORb) -Rc is usually carried out by dissolving the α-iminocarbonyl compound (1) represented by the general formula (1) as a substrate in an inert solvent, In the presence of a transition metal complex and a base.

The solvent that can be used in this reaction is not particularly limited as long as it is inert and solubilizes the reaction raw material (substrate) and the catalyst system. Such solvents include:
For example, aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic hydrocarbons such as pentane, hexane, and octane; halogen-containing hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; ethers; and ethers such as THF (tetrahydrofuran) , Methanol, ethanol,
Alcohols such as 2-propanol, butanol, benzyl alcohol, acetonitrile, DMF (N, N-
Organic solvents containing a hetero atom such as dimethylformamide), N-methylpyrrolidone, pyridine and DMSO (dimethylsulfoxide).

Of the above, in the present invention, alcohol-based solvents are particularly preferred because the product is an alcohol. These solvents can be used alone or as a mixed solvent thereof.

The amount of the solvent to be used is determined depending on the solubility of the reaction substrate, economy and the like. For example, when using 2-propanol, the reaction can be carried out at a substrate concentration of as low as 1% or less and in a state close to no solvent containing only the substrate.
It can be used at 0 to 50% by weight.

The reaction is carried out in the presence of hydrogen gas or a compound donating hydrogen. When hydrogen gas is used, the hydrogen pressure in the system is 1 to 200 atm, preferably 3 to 100 atm.
It is desirable to carry out under atmospheric pressure. Examples of the compound that donates hydrogen include a hydride complex and a hydrogen storage alloy.

The reaction temperature is set at -3 in consideration of the reaction rate and the like.
It is 0-100 degreeC, Preferably it is 15-100 degreeC. It can also be carried out near room temperature of 25 ° C to 40 ° C. The reaction varies depending on the reaction conditions such as the concentration of the reaction substrate, temperature and pressure, but is usually completed in a few minutes to 10 hours.

By reducing the β-imino alcohol represented by the general formula (2), the compound represented by the general formula (3):
Β represented by C * H (OH) —C * H (NH ₂ ) —Rc
In the reaction for obtaining an amino alcohol, it is preferable to use a heterogeneous metal catalyst, metal hydride or boron compound.

Examples of such a heterogeneous metal catalyst include palladium on carbon, palladium hydroxide, nickel,
Platinum or the like can be used. These heterogeneous metal catalysts are used in an amount of 0.01 to 1 (w / w), preferably 0.05 to 1 with respect to the β-imino alcohol represented by the general formula (2).
The reduction reaction can be performed using 0.3 (w / w) hydrogen at normal pressure to 100 atm, preferably normal pressure to 10 atm.

As the metal hydride, for example, LiAl
Aluminum hydrides such as H ₄ and DIBAL (diisobutylaluminum hydride), LiBH ₄ and NaB
Alkali metal borohydrides such as H ₄ , and metal hydrides such as calcium hydride and nickel hydride can be used.

As the boron compound, for example, 9-
Boron hydrides such as BBN (9-borabicyclo [3.3.1] nonane) and borane (BH ₃ or BH _3. (CH ₃ ) ₂ S complex or the like) can be used.

The α-iminocarbonyl compound (1)
In the case of obtaining β-amino alcohol (3) from the above, β-imino alcohol (2), which is a reaction intermediate, is once isolated and further reduced to obtain β-amino alcohol (2).
-Amino alcohol (3) can be obtained or can be used as it is in one pot (that is, β-imino alcohol (2)
Reaction without isolation)
β-amino alcohol (3) can also be obtained. In the case where the optically active β-imino alcohol represented by the general formula (2) is industrially mass-produced, the reaction system may be a batch system or a continuous system.

The β- produced by the production method of the present invention
Table 1 shows specific examples of the imino alcohol (2) and the starting compound (1).

[0086]

[Table 1]

[0087]

[Table 2]

[0088]

[Table 3]

[0089]

[Table 4]

[0090]

[Table 5]

[0091]

[Table 6]

[0092]

[Table 7]

[0093]

[Table 8]

[0094]

[Table 9]

[0095]

[Table 10]

Table 2 shows specific examples of the β-amino alcohol (3) and the starting compound (1) produced by the production method of the present invention.

[0097]

[Table 11]

[0098]

[Table 12]

[0099]

[Table 13]

[0100]

[Table 14]

[0101]

[Table 15]

[0102]

[Table 16]

[0103]

[Table 17]

[0104]

[Table 18]

[0105]

[Table 19]

[0106]

[Table 20]

[0107]

Next, the present invention will be described in more detail by way of examples. In the following examples, “BINAP”
Is 2,2'-bis- (diphenylphosphino) -1,
Represents 1′-binaphthyl, “TolBINAP” is
2,2′-bis (di-4-tolylphosphino) -1,
Represents 1′-binaphthyl, and “DPEN” is 1,
Represents 2-diphenylethylenediamine.

Example 1 (1S) -1-phenyl-2-
Production of (benzyloxyimino) propanol

[0109]

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(In the formula, * represents an asymmetric carbon atom.) 8 ml of 2-propanol, [(S) -BINAP] Ru
(II) Cl ₂ [(S, S) DPEN] 14.7 mg
(0.0146 mmol), 0.74 ml of ^t BuOK in 2-propanol (0.25 N), and 740 mg of 2- (benzyloxyimino) propiophenone (2.
90 mmol) was placed in a 100 ml autoclave under an argon atmosphere, and hydrogen was injected to 12 atm.
After stirring at 25 ° C. for 18 hours, the reaction mixture was separated and purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to obtain (1)
S) -1-phenyl-2- (benzyloxyimino) propanol 680 mg (2.66 mmol; yield 91)
%).

Example 2 Preparation of (1S, 2R) -1-phenyl-2- (benzoylamino) -1-propanol {(+)-norephedrine-N-benzoyl derivative}

[0112]

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(In the formula, * represents an asymmetric carbon atom.) T of 680 mg (2.66 mmol) of optically active 1-phenyl-2- (benzyloxyimino) propanol
0.57 ml (5.3 mmol) of a THF solution (10 N) of a borane-dimethylsulfide complex is added to 7 ml of the HF solution.
l) was added at 0 ° C. and then stirred at room temperature for 18 hours. 3N hydrochloric acid was added to the reaction solution to stop the reaction, the reaction solution was made basic with caustic soda, and then extracted and separated with chloroform. To the separated chloroform solution, 8 ml of a chloroform solution of triethylamine (0.93 ml; 6.6 mmol) and benzoic acid chloride (373 mg; 2.65 mm)
ol) at 0 ° C. and allowed to react for 4 hours. This solution was poured into water and separated, the organic layer was separated, and the aqueous layer was further extracted with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. When ¹ H-NMR of the obtained crude product was measured, anti isomer: syn isomer = 71: 29 (anti isomer δ = 5.0, syn isomer δ =
4.7). This crude product is subjected to silica gel column chromatography (eluent: hexane: ethyl acetate =
2: 1) and 450 mg of anti-1-phenyl-2- (benzoylamino) -1-propanol (1.
55 mmol; 58% yield). This one is Chi
It was 87% ee when analyzed by the racecel OJ column (eluent: hexane: ethanol = 10: 1).

Example 3 Production of (1S) -1- (4-methoxyphenyl) -2- (benzyloxyimino) propanol

[0115]

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(In the formula, * represents an asymmetric carbon atom.) 8 ml of 2-propanol, [(S) -TolBINAP
] Ru (II) Cl ₂ [(S, S) DPEN], 15.9
mg (0.0150 mmol), 1.5 ml (0.5 N) of ^t BuOK in 2-propanol, and 2- (benzyloxyimino) -p-methoxypropiophenone 8
50 mg (3.00 mmol) was added under argon atmosphere.
It was placed in a 00 ml autoclave and hydrogen was injected to 12 atm. After stirring at 25 ° C. for 18 hours, the reaction mixture was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to give (1.
829 mg (2.91 mm) of S) -1- (4-methoxyphenyl) -2- (benzyloxyimino) propanol
ol; yield 97%).

Example 4 Production of (1S, 2R) -1- (4-methoxyphenyl) -2- (benzoylamino) -1-propanol

[0118]

Embedded image

(In the formula, * represents an asymmetric carbon atom.) (1S) -1- (4-methoxyphenyl) -2- (benzyloxyimino) propanol 8 obtained in Example 1
12 mg of 29 mg (2.91 mmol) of THF solution
Then, a borane-dimethylsulfide complex THF solution (10
N) was added at 0 ° C. at 0.29 ml (2.9 mmol),
Thereafter, the mixture was stirred at 50 ° C. for 18 hours. The reaction was stopped by adding 3N hydrochloric acid, the reaction solution was made basic with an aqueous solution of sodium hydroxide, and extracted with chloroform. After the chloroform solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 462 mg of a mixture of the title compound and its isomer (2.1 mg) was obtained.
2 mmol; yield 73%, anti isomer: syn isomer = 84: 16). The mixing ratio of the isomers is ¹
According to the H-NMR spectrum, δ = 4.47 ppm for the anti isomer and δ for the syn isomer
= 4.17 ppm, a characteristic peak was observed, and the peak intensities of both peaks were quantified.

Next, a chloroform solution 6 of this mixture and 0.89 ml (6.4 mmol) of triethylamine was prepared.
358 mg (2.54 mg) of benzoic acid chloride at 0 ° C.
mmol) and reacted for 4 hours. The reaction solution was poured into water, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the chloroform layer were combined, dried over anhydrous magnesium sulfate, and concentrated, and the obtained residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 2: 1) as anti-1- (4 -Methoxyphenyl) -2- (benzoylamino) -1-propanol was obtained in an amount of 512 mg (1.59 mmol; yield: 75%). This was analyzed using a Chiralcel OJ column (eluent; hexane: ethanol = 10: 1), and the optical purity was 91% ee.

[0121]

As described above, according to the present invention,
The optically active β-imino alcohol represented by the general formula (2) and the optically active β-amino alcohol represented by the general formula (3), which are useful as intermediates for the synthesis of pharmaceuticals and agricultural chemicals, can be produced in a highly selective and high Can be manufactured to rate.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) C07C 251/50 C07C 251/50 // C07B 61/00 300 C07B 61/00 300 F term (reference) 4G069 AA03 AA06 BA08B BA27A BA27B BA47A BB08A BC65A BC69A BD01A BD07A BD08A BD11A BE08A BE14A BE26A BE33A CB02 4H006 AA02 AC11 AC41 BA41 BA03 BA06 BA23 BA24 BA26 BA61 BE20 BW11 BW18 4H039 CA60 CB20

Claims (18)

[Claims] 1. A compound of the general formula (1) (In the formula, Ra, Rb and Rc each independently represent an alkyl group optionally having a substituent, an alkenyl group optionally having a substituent, or a cyclo group optionally having a substituent. Represents an alkyl group, an aralkyl group which may have a substituent or an aryl group which may have a substituent, wherein Ra and Rc or Rb and Rc are bonded to form 5 to 8;
A member ring may be formed. A) reacting hydrogen with the α-iminocarbonyl compound represented by the general formula (2) in the presence of an optically active transition metal compound and a base. (Wherein Ra, Rb and Rc have the same meanings as described above,
C * represents an asymmetric carbon atom. ) Represented by the optically active β-
A method for producing imino alcohol. 2. A compound of the general formula (1) (In the formula, Ra, Rb and Rc each independently represent an alkyl group optionally having a substituent, an alkenyl group optionally having a substituent, or a cyclo group optionally having a substituent. Represents an alkyl group, an aralkyl group which may have a substituent or an aryl group which may have a substituent, wherein Ra and Rc or Rb and Rc are bonded to form 5 to 8;
A member ring may be formed. ) Is reacted with hydrogen in the presence of an optically active transition metal compound and a base to give a compound of the general formula (2) (Wherein Ra, Rb and Rc have the same meanings as described above,
C * represents an asymmetric carbon atom. ), And a step of reducing the obtained β-imino alcohol. (Wherein Ra, Rc and C * have the same meanings as described above).
-A process for producing amino alcohols. 3. The method for producing optically active β-imino alcohol according to claim 1, wherein said optically active transition metal compound is a homogeneous optically active hydrogenation catalyst. 4. The method for producing an optically active β-amino alcohol having an anti-configuration according to claim 2, wherein the optically active transition metal compound is a homogeneous optically active hydrogenation catalyst. 5. The optically active homogeneous hydrogenation catalyst is represented by the general formula (4): (In the formula, Ma represents a Group VIII metal, X and Y each independently represent a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group or an alkoxy group, and m and n each independently represent 0 Or an integer of 1 to 4, Px represents a phosphine ligand, and Nx represents an amine ligand.
At least one of Px and Nx is an optically active ligand. 4. The method for producing an optically active β-imino alcohol according to claim 3, which is a compound represented by the formula: 6. The optically active homogeneous hydrogenation catalyst is represented by the general formula (4): (In the formula, Ma represents a Group VIII metal, X and Y each independently represent a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group or an alkoxy group, and m and n each independently represent 0 Or an integer of 1 to 4, Px represents a phosphine ligand, and Nx represents an amine ligand.
At least one of Px and Nx is an optically active ligand. 5. The method for producing an optically active β-amino alcohol having an anti-configuration according to claim 4, which is a compound represented by the formula: 7. The method for producing an optically active β-imino alcohol according to claim 1, wherein the Px is an optically active phosphine ligand. 8. The method for producing an optically active β-amino alcohol having an anti-configuration according to claim 2, wherein the Px is an optically active phosphine ligand. 9. The method for producing an optically active β-imino alcohol according to claim 1, wherein the Nx is an optically active amine ligand. 10. The method for producing an optically active β-amino alcohol having an anti-configuration according to claim 2, wherein the Nx is an optically active amine ligand. 11. The base represented by the general formula (5): (Wherein, Mb represents an alkali metal or an alkaline earth metal, and Z represents a hydroxyl group, an alkoxy group, or a mercapto group). The method for producing an optically active β-imino alcohol according to any one of the above. 12. The base represented by the general formula (5): (Wherein, Mb represents an alkali metal or an alkaline earth metal, and Z represents a hydroxyl group, an alkoxy group, or a mercapto group). The method for producing an optically active β-amino alcohol having an anti-configuration according to any one of the above. 13. The method of reducing β-imino alcohol according to claim 2, wherein the step of reducing β-imino alcohol comprises a step of causing hydrogen to act on β-imino alcohol represented by the general formula (2). Or a method for producing an optically active β-amino alcohol having an anti-configuration according to any one of the above. 14. The step of reducing the β-imino alcohol includes the step of causing hydrogen to act on the β-imino alcohol represented by the general formula (2) in the presence of a metal-based reagent. Optically active β having an anti-configuration described in
-A process for producing amino alcohols. 15. The optically active β-anti-configuration metal according to claim 14, wherein said metal-based reagent is a heterogeneous metal catalyst.
Method for producing amino alcohol. 16. The optically active β-anti-configuration reagent according to claim 14, wherein the metal-based reagent is a metal hydride.
Method for producing amino alcohol. 17. The method of reducing β-imino alcohol according to claim 2, wherein the step of reducing β-imino alcohol comprises a step of reacting a β-imino alcohol represented by the general formula (2) with a boron compound. 13. A method for producing an optically active β-amino alcohol having an anti-configuration according to any of 10 or 12. 18. The optically active β-anti-configuration having the anti-configuration according to claim 18, wherein the boron compound is borane.
Method for producing amino alcohol.